Antibodies That Impair Insulin Receptor Binding in an Unusual Diabetic Syndrome with Severe Insulin Resistance

Flier, J. S.; Kahn, C. Ronald; Roth, Jesse; Bar, Robert S.

doi:10.1126/science.170678

Cited by 420 publications

(177 citation statements)

References 20 publications

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“…Insulin resistance is present in humans with obesity, metabolic syndrome, and T2D, and in the latter can be detected years before the clinical presentation of disease (2,22), suggesting a primary role in the pathophysiology of T2D. Severe forms of insulin resistance are observed in patients with genetic mutations in the insulin receptor or anti-insulin receptor antibodies (1,(23)(24)(25), and these have been highly informative in our understanding of insulin signaling pathways and the impact of insulin resistance on systemic metabolism. The molecular mechanisms underlying insulin resistance in these disorders may include both acquired and genetic components; however, dissecting the relative contributions of each is difficult due to the lack of robust and reliable models for the study of disease pathogenesis in humans in vitro.…”

Section: Discussionmentioning

confidence: 99%

Myotubes derived from human-induced pluripotent stem cells mirror in vivo insulin resistance

Iovino

Burkart

Warren

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Induced pluripotent stem cells (iPS cells) represent a unique tool for the study of the pathophysiology of human disease, because these cells can be differentiated into multiple cell types in vitro and used to generate patient- and tissue-specific disease models. Given the critical role for skeletal muscle insulin resistance in whole-body glucose metabolism and type 2 diabetes, we have created a novel cellular model of human muscle insulin resistance by differentiating iPS cells from individuals with mutations in the insulin receptor (IR-Mut) into functional myotubes and characterizing their response to insulin in comparison with controls. Morphologically, IR-Mut cells differentiated normally, but had delayed expression of some muscle differentiation-related genes. Most importantly, whereas control iPS-derived myotubes exhibited in vitro responses similar to primary differentiated human myoblasts, IR-Mut myotubes demonstrated severe impairment in insulin signaling and insulin-stimulated 2-deoxyglucose uptake and glycogen synthesis. Transcriptional regulation was also perturbed in IR-Mut myotubes with reduced insulin-stimulated expression of metabolic and early growth response genes. Thus, iPS-derived myotubes from individuals with genetically determined insulin resistance demonstrate many of the defects observed in vivo in insulin-resistant skeletal muscle and provide a new model to analyze the molecular impact of muscle insulin resistance.

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Section: Discussionmentioning

confidence: 99%

Myotubes derived from human-induced pluripotent stem cells mirror in vivo insulin resistance

Iovino

Burkart

Warren

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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“…The type B insulin resistance syndrome is an autoimmune phenomenon caused by polyclonal immunoglobulin G antibodies with antagonist activity directed against the insulin receptor (1,2,4). This competition results in hypersecretion of insulin to compensate, usually at insufficient levels to maintain normoglycemia (1,2,(18)(19)(20). Occasionally, the receptor autoantibodies can have an insulin-like effect, which can cause hypoglycemia (21)(22)(23)(24).…”

mentioning

confidence: 99%

Treatment of systemic lupus erythematosus–associated type B insulin resistance syndrome with cyclophosphamide and mycophenolate mofetil

Gehi¹,

Webb²,

Nolte³

et al. 2003

Arthritis & Rheumatism

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Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by loss of immunologic self-tolerance and the subsequent development of autoantibodies. These antibodies are thought to be important in relation to the clinical manifestations of the disease. One example is the development of multiple cytopenias secondary to cytolytic or cytotoxic antibodies directed toward red blood cells, platelets, and white blood cells. Other antibodies may mediate abnormal cellular mechanisms such as those seen with neuropsychiatric manifestations of SLE. We report the occurrence of autoantibodies directed toward insulin receptors and the subsequent development of type B insulin resistance syndrome in a woman with SLE. This syndrome was treated successfully with cyclophosphamide and mycophenolate mofetil.

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“…Insulin initiates its effects by interacting with receptors located on the plasma membrane [1][2][3] and altered insulin receptor interaction may be responsible for hormone resistance [4][5][6][7][8][9][10][11][12][13][14].…”

mentioning

confidence: 99%

Insulin antibodies prevent insulin-receptor interactions

et al. 1980

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Summary. The study was carried out to investigate whether insulin bound to antibody is able to bind the insulin receptor of target tissues. Three specific rabbit anti-insulin sera as well as sera from eight diabetic patients with insulin antibodies were incubated, free of insulin, with labelled insulin for 48 h at 4 ~ following incubation labelled insulin was employed in binding experiments on monocytes, erythrocytes and placenta membranes. Using rabbit sera, receptor binding was absent when insulin was totally combined with antibody, and appeared in increasing amounts as the percentage of free insulin increased to reach a maximum when no insulin was combined with antibody. The same experiment using sera from diabetic patients showed a close negative relationship (r = 0.95) between the amount of insulin bound to the antibody and the amount bound to receptors. The influence of the insulin-antibody complex on the insulin receptor interaction was evaluated by exposing the insulin-antibody complex to the receptor in pH, temperature and competition-inhibition curve experiments. The complex had no effect on receptor affinity or on the pH and temperature relationship influence with insulin-receptor interaction. The findings suggest that insulin resistance in the presence of insulin antibodies is due only to an alteration occurring before the interaction of insulin with its receptor, and demonstrate that the insulin-antibody complex does not influence the insulin receptor interaction.

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Antibodies That Impair Insulin Receptor Binding in an Unusual Diabetic Syndrome with Severe Insulin Resistance

Cited by 420 publications

References 20 publications

Myotubes derived from human-induced pluripotent stem cells mirror in vivo insulin resistance

Myotubes derived from human-induced pluripotent stem cells mirror in vivo insulin resistance

Treatment of systemic lupus erythematosus–associated type B insulin resistance syndrome with cyclophosphamide and mycophenolate mofetil

Insulin antibodies prevent insulin-receptor interactions

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